Prospective Exploratory Analysis of Angiogenic Biomarkers in Peripheral Blood in Advanced NSCLC Patients Treated With Bevacizumab Plus Chemotherapy: The ANGIOMET Study

[EN] Finding angiogenic prognostic markers in advanced non-small-cell lung cancer is still an unmet medical need. We explored a set of genetic variants in the VEGF-pathway as potential biomarkers to predict clinical outcomes of patients with non-small-cell lung cancer treated with chemotherapy plus bevacizumab. We prospectively analyzed the relationship between VEGF-pathway components with both pathological and prognostic variables in response to chemotherapy plus bevacizumab in 168 patients with non-squamous non-small-cell lung cancer. Circulating levels of VEGF and VEGFR2 and expression of specific endothelial surface markers and single-nucleotide polymorphisms in VEGF-pathway genes were analyzed. The primary clinical endpoint was progression-free survival. Secondary endpoints included overall survival and objective tumor response. VEGFR-1 rs9582036 variants AA/AC were associated with increased progression-free survival (p = 0.012 and p = 0.035, respectively), and with improved overall survival (p = 0.019) with respect to CC allele. Patients with VEGF-A rs3025039 harboring allele TT had also reduced mortality risk (p = 0.049) compared with the CC allele. The VEGF-A rs833061 variant was found to be related with response to treatment, with 61.1% of patients harboring the CC allele achieving partial treatment response. High pre-treatment circulating levels of VEGF-A were associated with shorter progression-free survival (p = 0.036). In conclusion, in this prospective study, genetic variants in VEGFR-1 and VEGF-A and plasma levels of VEGF-A were associated with clinical benefit, progression-free survival, or overall survival in a cohort of advanced non-squamous non-small-cell lung cancer patients receiving chemotherapy plus antiangiogenic therapy.The authors thank Drs. Blanca Piedrafita and Vanessa Marfil at Medical Statistics Consulting for medial writing services. RR also wish to acknowledge the support by the Asociacion Espanola Contra el Cancer (AECC).Jantus-Lewintre, E.; Massuti Sureda, B.; Gonzalez Larriba, JL.; Rodríguez-Abreu, D.; Juan, O.; Blasco, A.; Domine, M.... (2021). Prospective Exploratory Analysis of Angiogenic Biomarkers in Peripheral Blood in Advanced NSCLC Patients Treated With Bevacizumab Plus Chemotherapy: The ANGIOMET Study. Frontiers in Oncology. 11:1-11. https://doi.org/10.3389/fonc.2021.695038S1111

Morfometría de cladodios de nopal cultivado en Santander - Colombia: estudio exploratorio

The prickly pear, a fleshy plant with widely researched nutritional and therapeutic properties at the industrial level, is cultivated abundantly in the municipality of La Mesa de los Santos -Santander in Colombia, because to the arid conditions of the area. The main purpose of this study was to carry out a detailed morphometric characterization of the nopal cladode, which is a cactus branch resembling a leaf, and to analyze the nutritional and microbiological properties of the flour produced from Opuntia ficus-indica (L.) Miller. A total of 108 cladodes, each with a length greater than 30 cm, were processed, analyzing variables such as weight, length, and thickness. Additionally, bromatological values, including ash content, moisture, crude fiber, calcium, acidity, and protein, were determined. The presence of microorganisms was assessed through aerobic microorganism counts, identification of aerobic and anaerobic bacteria, yeast, and fungi analysis. The results of the morphometric analysis revealed a significant correlation between weight and width (with a correlation coefficient of r = 0,80) and the vertical length of the nopal cladodes (r = 0,72). Regarding the bromatological characterization of nopal flour, the obtained values were as follows: moisture 11,7 %, ash 1,54 %, fat 2,3 %, protein 6,2 %, crude fiber 8,2 %, total carbohydrates 64,22 %, and acidity 0,12 %. As for the microbiological analysis of nopal flour, values were reported below the allowed limits for mesophilic aerobic microorganisms, total coliforms, E. coli, molds, and yeasts. This study provides fundamental information about nopal cultivation in La Mesa de los Santos-Santander, highlighting its potential as a food source through morphometric analysis, by estimating the weight of the crops without causing damage to them, in addition to nutritional analysis. These findings are of great local significance, and it is hoped that future research will promote the use and further knowledge of this plant.El nopal, es una planta carnosa con propiedades nutricionales y terapéuticas ampliamente investigada a nivel industrial. En Colombia, se cultiva en abundancia en el municipio de La Mesa de los Santos-Santander, gracias a las condiciones desérticas de la zona. El propósito principal de este estudio fue llevar a cabo una detallada caracterización morfométrica del cladodio de nopal, que es una rama del cactus, con apariencia de hoja y analizar las propiedades nutricionales y microbiológicas de la harina producida a partir de Opuntia ficus-indica (L.) Miller. Por lo cual, se procesaron un total de 108 cladodios, con longitud superior a los 30 cm, analizando las variables: peso, longitud y grosor. Adicionalmente, se determinaron valores bromatológicos como ceniza, humedad, fibra cruda, calcio, acidez y proteína. La presencia de microorganismos se determinó por medio de recuento de microorganismos aerobios; identificación de bacterias aerobias y anaerobias; análisis de levaduras y algunos hongos. Los resultados del análisis morfométrico revelaron una correlación significativa entre el peso; el ancho (con un coeficiente de correlación r = 0,80) y la longitud vertical de los cladodios del nopal (r = 0,72). En cuanto a la caracterización bromatológica de la harina de nopal, los valores obtenidos fueron: humedad 11.7%, ceniza 154 %, grasa 2,3 %, proteína 6,2 %, fibra cruda 8,2 %, carbohidratos totales 64,22 %, acidez 0,12 %. En cuanto al análisis microbiológico de la harina de nopal se reportan valores por debajo de los límites permitidos para presencia de microrganismos aerobios mesófilos, coliformes totales, Escherichia coli, mohos y levaduras. Este estudio permite tener información base sobre el cultivo de nopal producido en La Mesa de los Santos - Santander, develando su potencial alimentico sustentado en el análisis morfométrico, al estimar el peso de los cultivos sin causarles daño, y complementado con el análisis nutricional. Estos hallazgos son de gran relevancia a nivel local, por lo cual se espera que futuras investigaciones promuevan el uso y profundización del conocimiento de esta planta

Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries

IMPORTANCE: Limited information exists about the epidemiology, recognition, management, and outcomes of patients with the acute respiratory distress syndrome (ARDS). OBJECTIVES: To evaluate intensive care unit (ICU) incidence and outcome of ARDS and to assess clinician recognition, ventilation management, and use of adjuncts-for example prone positioning-in routine clinical practice for patients fulfilling the ARDS Berlin Definition. DESIGN, SETTING, AND PARTICIPANTS:The Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients undergoing invasive or noninvasive ventilation, conducted during 4 consecutive weeks in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across 5 continents. EXPOSURES:Acute respiratory distress syndrome. MAIN OUTCOMES AND MEASURES: The primary outcome was ICU incidence of ARDS. Secondary outcomes included assessment of clinician recognition of ARDS, the application of ventilatory management, the use of adjunctive interventions in routine clinical practice, and clinical outcomes from ARDS. RESULTS: Of 29,144 patients admitted to participating ICUs, 3022 (10.4%) fulfilled ARDS criteria. Of these, 2377 patients developed ARDS in the first 48 hours and whose respiratory failure was managed with invasive mechanical ventilation. The period prevalence of mild ARDS was 30.0% (95% CI, 28.2%-31.9%); of moderate ARDS, 46.6% (95% CI, 44.5%-48.6%); and of severe ARDS, 23.4% (95% CI, 21.7%-25.2%). ARDS represented 0.42 cases per ICU bed over 4 weeks and represented 10.4% (95% CI, 10.0%-10.7%) of ICU admissions and 23.4% of patients requiring mechanical ventilation. Clinical recognition of ARDS ranged from 51.3% (95% CI, 47.5%-55.0%) in mild to 78.5% (95% CI, 74.8%-81.8%) in severe ARDS. Less than two-thirds of patients with ARDS received a tidal volume 8 of mL/kg or less of predicted body weight. Plateau pressure was measured in 40.1% (95% CI, 38.2-42.1), whereas 82.6% (95% CI, 81.0%-84.1%) received a positive end-expository pressure (PEEP) of less than 12 cm H2O. Prone positioning was used in 16.3% (95% CI, 13.7%-19.2%) of patients with severe ARDS. Clinician recognition of ARDS was associated with higher PEEP, greater use of neuromuscular blockade, and prone positioning. Hospital mortality was 34.9% (95% CI, 31.4%-38.5%) for those with mild, 40.3% (95% CI, 37.4%-43.3%) for those with moderate, and 46.1% (95% CI, 41.9%-50.4%) for those with severe ARDS. CONCLUSIONS AND RELEVANCE: Among ICUs in 50 countries, the period prevalence of ARDS was 10.4% of ICU admissions. This syndrome appeared to be underrecognized and undertreated and associated with a high mortality rate. These findings indicate the potential for improvement in the management of patients with ARDS

J-PLUS: A first glimpse at spectrophotometry of asteroids -- The MOOJa catalog

Context: The Javalambre Photometric Local Universe Survey (J-PLUS) is an observational campaign that aims to obtain photometry in 12 ultraviolet-visible filters (0.3-1 {\mu}m) of approximately 8 500 deg{^2} of the sky observable from Javalambre (Teruel, Spain). Due to its characteristics and strategy of observation, this survey will let us analyze a great number of Solar System small bodies, with improved spectrophotometric resolution with respect to previous large-area photometric surveys in optical wavelengths. Aims: The main goal of this work is to present here the first catalog of magnitudes and colors of minor bodies of the Solar System compiled using the first data release (DR1) of the J-PLUS observational campaign: the Moving Objects Observed from Javalambre (MOOJa) catalog. Methods: Using the compiled photometric data we obtained very-low-resolution reflectance (photospectra) spectra of the asteroids. We first used a {\sigma}-clipping algorithm in order to remove outliers and clean the data. We then devised a method to select the optimal solar colors in the J-PLUS photometric system. These solar colors were computed using two different approaches: on one hand, we used different spectra of the Sun, convolved with the filter transmissions of the J-PLUS system, and on the other, we selected a group of solar-type stars in the J-PLUS DR1, according to their computed stellar parameters. Finally, we used the solar colors to obtain the reflectance spectra of the asteroids. Results: We present photometric data in the J-PLUS filters for a total of 3 122 minor bodies (3 666 before outlier removal), and we discuss the main issues of the data, as well as some guidelines to solve the

Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks

Background: A systems biology approach based on the assembly and interrogation of gene regulatory networks, or interactomes, was used to study neuroadaptation processes associated with the transition to alcohol dependence at the molecular level. Results: Using a rat model of dependent and non-dependent alcohol self-administration, we reverse engineered a global transcriptional regulatory network during protracted abstinence, a period when relapse rates are highest. We then interrogated the network to identify master regulator genes that mechanistically regulate brain region-specific signatures associated with dependent and non-dependent alcohol self-administration. Among these, the gene coding for the glucocorticoid receptor was independently identified as a master regulator in multiple brain regions, including the medial prefrontal cortex, nucleus accumbens, central nucleus of the amygdala, and ventral tegmental area, consistent with the view that brain reward and stress systems are dysregulated during protracted abstinence. Administration of the glucocorticoid antagonist mifepristone in either the nucleus accumbens or ventral tegmental area selectively decreased dependent, excessive, alcohol self-administration in rats but had no effect on non-dependent, moderate, alcohol self-administration. Conclusions: Our study suggests that assembly and analysis of regulatory networks is an effective strategy for the identification of key regulators of long-term neuroplastic changes within specific brain regions that play a functional role in alcohol dependence. More specifically, our results support a key role for regulatory networks downstream of the glucocorticoid receptor in excessive alcohol drinking during protracted alcohol abstinence

Improving Breast Cancer Survival Analysis through Competition-Based Multidimensional Modeling

Breast cancer is the most common malignancy in women and is responsible for hundreds of thousands of deaths annually. As with most cancers, it is a heterogeneous disease and different breast cancer subtypes are treated differently. Understanding the difference in prognosis for breast cancer based on its molecular and phenotypic features is one avenue for improving treatment by matching the proper treatment with molecular subtypes of the disease. In this work, we employed a competition-based approach to modeling breast cancer prognosis using large datasets containing genomic and clinical information and an online real-time leaderboard program used to speed feedback to the modeling team and to encourage each modeler to work towards achieving a higher ranked submission. We find that machine learning methods combined with molecular features selected based on expert prior knowledge can improve survival predictions compared to current best-in-class methodologies and that ensemble models trained across multiple user submissions systematically outperform individual models within the ensemble. We also find that model scores are highly consistent across multiple independent evaluations. This study serves as the pilot phase of a much larger competition open to the whole research community, with the goal of understanding general strategies for model optimization using clinical and molecular profiling data and providing an objective, transparent system for assessing prognostic models

IRE1α-XBP1 Activation Elicited by Viral Singled Stranded RNA via TLR8 May Modulate Lung Cytokine Induction in SARS-CoV-2 Pneumonia

Initial symptoms of COVID-19 infection depend on viral replication, while hyperinflammation is a hallmark of critical illness and may drive severe pneumonia and death. Among the mechanisms potentially involved in the hyperinflammatory state, we focused on the unfolded protein response, because the IRE1α-XBP1 branch can be activated as result of the endoplasmic reticulum stress produced by the overwhelming synthesis of viral components and synergizes with Toll-like receptor signaling to induce cytokine expression. Viral RNA may trigger the IRE1α-XBP1 branch via TLR7/8 activation and like TLR2 and TLR4 may underpin cytokine expression trough XBP1 splicing (sXBP1). The expression of IL1B, IL6, and TNF mRNA in bronchoalveolar aspirates (BAAs) were higher in COVID-19 patients under mechanical ventilation and intubation who showed sXBP1. The scrutiny of monocytic/macrophagic markers during active infection showed a reduction of those involved in antigen presentation and survival, as well as the IFN stimulated gene MX1. These changes reverted after infection tests turned negative. In contrast, the expression of the mRNA of the serine protease TMPRSS2 involved in S protein priming showed a high expression during active infection. TLR8 mRNA showed an overwhelming expression as compared to TLR7 mRNA, which suggests the presence of monocyte-derived dendritic cells (MDDCs). In vitro experiments in MDDCs activated with ssRNA40, a positive-sense, single-stranded RNA (+ssRNA) like SARS-CoV-2 RNA, induced sXBP1 and the expression of IL-1β, IL-6, and TNFα at mRNA and protein levels. These responses were blunted by the IRE1α ribonuclease inhibitor MKC8866. Given the analogies between the results observed in BAAs and the effects induced by +ssRNA in MDDCs, IRE1α ribonuclease inhibition might be a druggable target in severe COVID-19 disease.This study was funded by Fondo COVID-19 del Instituto de Salud Carlos III/Junta de Castilla y Leon (N.F.). European Commission-NextGenerationEU, through CSIC's Global Health Platform (PTI Salud Global) (project SGL2103016) (M.S.C.). Plan Nacional de Salud y Farmacia Grant SAF2017-83079-R and Grant PID2020-113751RB-I00 funded by MCIN/AEI/ 10.13039/501100011033 (M.S.C.). Junta de Castilla y Leon/Fondo Social Europeo Grants CSI035P17 (M.S.C.) and VA175P20 (N.F.). Proyecto SEAHORSE INFRARED: IR2020-1-UVA05 (JCyL).N

Introducción a los análisis espaciales con énfasis en modelos de nicho ecológico

En 2016 implementamos un sistema de seminarios de enseñanza, en formato de videos libres y accesibles desde internet, con la finalidad de dar a conocer de forma sencilla y en castellano, las bases conceptuales y aplicaciones de los modelos de nicho ecológico en estudios de ecología, conservación biológica, epidemiología y agrobiodviersidad, así como su implementación para el diseño de políticas públicas de los recursos naturales. Cada seminario fue desarrollado por uno o varios expertos discutiendo conceptos, métodos y diferentes herramientas disponibles para elaborar modelos de distribución de especies. Este manuscrito reúne los resúmenes de cada uno de los seminarios en línea, dando referencias clave para cada tema y el enlace al video correspondiente. Los videos están disponibles de forma libre en YouTube o en formato .mp4 bajo solicitud

MVA-CoV2-S vaccine candidate confers full protection from SARS-CoV-2 brain infection and damage in susceptible transgenic mice

The protective efficacy of vaccines against SARS-CoV-2 infection in the brain is yet unclear. Here, in the susceptible transgenic K18-hACE2 mouse model of severe COVID-19 disease, we report a detailed spatiotemporal description of the SARS-CoV-2 infection and replication in different areas of the brain. Remarkably, SARS-CoV-2 brain replication occurs primarily in neurons, producing important neuropathological alterations such as neuronal loss, incipient signs of neuroinflammation, and vascular damage in SARS-CoV-2 infected mice. Notably, one or two doses of a modified vaccinia virus Ankara (MVA) vector expressing the SARS-CoV-2 spike (S) protein (MVA-CoV2-S) conferred full protection against SARS-CoV-2 cerebral infection, preventing virus replication in all areas of the brain and its associated damage. This protection was maintained even after SARS-CoV-2 reinfection. To our knowledge, this is the first study of a COVID-19 vaccine candidate showing 100% efficacy against SARS-CoV-2 brain infection and damage, reinforcing the use of MVA-CoV2-S as a promising vaccine candidate against SARS-CoV-2/COVID-19, worth to move forward into clinical trials.The authors thank the Centro de Investigación en Sanidad Animal (CISA)-Instituto Nacional de Investigaciones Agrarias (INIA-CSIC) (Valdeolmos, Madrid, Spain) for the BSL-3 facilities. SARS-CoV-2 MAD6 virus isolate was kindly provided by José M. Honrubia and Dr. Luis Enjuanes (CNB-CSIC, Madrid, Spain). We also thank to Dr. Konstantin L. Levitsky for excellent technical assistance with the confocal acquisition. We thank the Spanish Research Council (CSIC) and the Spanish Ministry of Science and Innovation (MICINN) for continuous support. This research was supported by MCIN/Spanish Research Agency (AEI)/ 10.13039/501100011033 grants: PID2019-105995RB-I00 (J.T.-A. and J.V.), PID2020- 114481RB-I00 (J.G.-A. and M.E.), and PID2019-106410RB-I00 (J.L.-B.). Moreover, this research work was also funded by Red TerCel ISCIII, RD16/0011/0025 (J.T.-A.); Consejería de Salud y Familias, Junta de Andalucía Grant, PECOVID-0078-2020 (R.R.-L. and J.V.); Fondo COVID-19 grant COV20/00151 [Spanish Health Ministry, Instituto de Salud Carlos III (ISCIII)], Fondo Supera COVID-19 (Crue Universidades-Banco Santander) grant and CSIC grant 202120E079 (J.G.-A.); and CSIC grant 2020E84, La CaixaImpulse grant CF01-00008, Ferrovial and MAPFRE donations (M.E.). Additionally, we have also funding from the European Commission-NextGenerationEU, through CSIC's Global Health Platform (PTI Salud Global) (J.G.-A. and M.E.) and the European Research Council (ERC Advanced Grant PRJ201502629) (J.L.-B.).N